Drugs that have been administered orally quickly pass through the esophagus to reach the stomach. The stomach walls are made from the 3 layers of mucous membrane, muscle layer, and serous membrane. However, in contrast to the small intestine, the effective surface area for absorption is small, and therefore, with the exception of some drugs, the stomach plays a small role as an absorption site. On the other hand, the small intestine of humans consists of the duodenum, jejunum, and ileum. It is the longest of the digestive tract and its effective surface area for absorption is large. Therefore, it is the ideal site for absorption of many drugs. However, epithelial cells, which have a plasma membrane made from a lipid double layer, cover the surface of the digestive tract mucous membrane site very closely and therefore, absorption is strongly restricted in the case of drugs that are very water soluble and polymer drugs. Moreover, in addition to the digestive tract mucous membrane, the mucous layer that ordinarily covers the digestive tract mucous membrane also becomes a barrier blocking the absorption of drugs by the digestive tract. Consequently, drugs that have been orally administered are first absorbed in vivo after passing through the above-mentioned two barriers of the mucous layer covering the mucous membrane surface and the mucous membrane.
The above-mentioned mucous layer is mainly made from the components of, glycoprotein such as mucin, cholesterol, lipids such as linoleic acid, proteins, DNA, and others, including various metal ions, such as calcium ions, etc. Moreover, the mucous membrane also contains traces of metal ions, etc. Consequently, drugs that are difficult to absorb through the digestive tract because of interaction with various biologically-derived components are present in the mucous layer and/or mucous membrane of the digestive tract.
For instance, bisphosphonate compounds have (P—C—P) bonds in their molecular structure and therefore, as with phosphonate compounds in general, have strong affinity with bivalent metal ions, such as calcium ions, etc., and bond with these metal ions to form insoluble complexes. Consequently, when bisphosphonate compounds are taken after eating or simultaneously with calcium agent, a slightly soluble complex is formed in the digestive tract and therefore, absorptivity of the bisphosphonate compound in the digestive tract is markedly reduced.
Moreover, it is known that there are cases where digestive tract absorption is blocked with substances that form complexes of inferior permeability of the mucous layer and mucous membrane, such as complexes of drugs and bile acids, etc.
Furthermore, the absorption route, solubility, lipophilicity, molecular weight, decomposition by digestive enzymes etc., of the drug are considered to be other factors that block digestive tract absorption.
The drug absorption routes include the route of passage through the cell membrane of mucous membrane cells and the route of passage through spaces between cells. In order for a drug to be absorbed, the drug must dissolve by either route. Consequently, drugs are slightly soluble and drugs that form an insoluble complex with in vivo components are difficult to absorb. In the case of the route of passage through the cell membrane, the drug must pass through the lipid membrane of the cell and therefore, drugs of low lipophilicity are generally difficult to absorb.
As explained above, there appear to be various reasons why drugs are difficult to absorb through the mucous layer and/or mucous membrane of the digestive tract.
The fact that drugs have difficulty passing through the mucous layer of the digestive tract has been reported many times in the past. For instance, J. Karlsson et al. report that the mucous layer accounts for 78% of the barrier to absorption of testosterone (Int. J. Pharm., 1993). Moreover, I. W. Kellaway et al. report that the mucous layer reduces bioavailability of tetracycline by 50% (J. Pharm. Pharmacol., 27 (4), pp. 281-283, 1975). Furthermore, A. W. Larhed et al. also report that the mucous layer reduces the diffusion coefficient of testosterone by 50% (J. Pharm. Sci, 86, pp.660-665, 1997). In addition, it is reported that bisphosphonate compounds form a chelate with calcium ions within the digestive tract to produce an insoluble complex and absorption from the digestive tract is thereby reduced (Br. J. Cancer, 71, Suppl. 24, 67, 1995). It is also reported that the absorption of pafenolol from the small intestine was inhibited by interaction with bile acids (Pharmaceutical Research, 10(6): pp. 879-83, 1993).
Consequently, enhancement of in vivo absorption of a drug by preventing interaction with the mucous layer or a substance present in the mucous layer or mucous membrane and/or enhancement of digestive tract absorption of a drug by improving drug permeability through cells and/or spaces between cells when the digestive tract mucous membrane is affected, targeted at drugs that are difficult to absorb from the digestive tract due to interaction with the digestive tract mucous layer and/or mucous membrane, including drugs that are difficult to absorb from the digestive tract because permeability of the mucous layer present on the digestive tract mucous membrane is poor, drugs that form an insoluble complex by interaction with a substance present in the mucous layer and are therefore difficult to absorb, drugs that are difficult to absorb from the digestive tract because of poor permeability of the mucous membrane of the digestive tract, etc., is an important technical topic in terms of hoping for satisfactory pharmacological activity from a drug.
On the other hand, the following methods are known as technology for improving permeability of drugs through the digestive tract mucous layer:
For instance, K. Morimoto et al., report increasing absorption of sulfaguanidine, phenol red or scopolamine by the addition hyaluronidase (J. Pharmacobiodyn, 9, No. 6, s-58, 1986), A Wikman et al. report reducing the mucous layer and improving permeability of testosterone by the addition of N-acetylcysteine (Pharm. Res., 10, No. 6, pp 843-852, (1993)), H. Asada et al. report improving permeability of the mucous layer of the duodenum and large intestine by modification of insulin with caproic acid (J. Pharm. Sci., 84, No. 6, pp. 682-687, 1995), and L. Hovgaard et al. report improving dispersion in the mucous layer by forming a compound of dodecyl maltoside and insulin (J. Controlled Release, 19, No. 1-3, pp. 99-108, 1992). Nevertheless, these methods are technologies for improving drug migration through the mucous layer by reducing the mucous layer or forming a specific drug complex and are not means for improving oral absorption by preventing interaction between a drug and components of the mucous layer and mucous membrane.
Furthermore, J. H. Lin et al. report that absorption of alendronate (4-amino-1-hydroxy butylidene 1,1-bisphosphonate), whose absorption is reduced due to the formation of a compound with calcium ions in vivo, is increased by chelators, such as EDTA, citric acid, etc. (Pharm. Res., 8, No. 10, Suppl., S273, 1991), but this method is simply technology that deals with chelators of specific drugs. Moreover, N. G. M. Schipper et al. report that chitosan, which are cationic natural polymers, have drug absorption-promoting effects as a tight-junction opener of the digestive tract mucous membrane in tests using Caco-2 cells. Nevertheless, it is reported that chitosan reduce drug permeability by interaction with the mucous layer in tests using HT-29 cells in vitro, and they do not improve oral absorption by preventing interaction between a drug and components of the mucous layer and mucous membrane of the digestive tract (Eur. J. Pharm. Sci., 8, No. 4, pp. 335-343, 1999).
On the other hand, aminoalkyl methacrylate copolymer E is a copolymer of methyl methacrylate and butyl methacrylate and dimethylaminoethyl methacrylate that was developed by Röhm, and is a polymer substance marketed under the brand name of Eudragit™ E100 or Eudragit™ EPO (both by Röhm GmbH).
Aminoalkyl methacrylate copolymer E is a famous film coating base that is commonly used to mask the bitter taste and color of tablets and granules and provide moisture resistance, etc., having the properties of (1) quickly dissolving in gastric juices and (2) dissolving in buffer with a pH of 5.0 or lower and expanding film in buffer at a pH of 5.0 or higher. Consequently, in addition to masking the bitter taste and color of drugs and providing moisture resistance, aminoalkyl methacrylate copolymer E is being used for solubilization of drugs, etc.
Moreover, aminoalkyl methacrylate copolymer E is used as a base that forms a solid dispersion in order to increase solubility of slightly soluble drugs.
Nevertheless, the fact that oral absorptivity is improved when aminoalkyl methacrylate copolymer E enhances permeability of drugs in the digestive tract mucous membrane and/or mucous layer was not known at all in the past.
In addition, aminoalkyl methacrylate copolymer E is a gastrosoluble polymer base and therefore, it has not been used to make pharmaceutical preparations by being mixed with acidic substances, which would degrade this function.
Incidentally, the following methods are known as technology for using aminoalkyl methacrylate copolymer E to improve oral absorption of drugs:
An invention relating to a solid dispersion consisting of 4″-O-paramethoxyphenylacetyl)tyrosine antibiotic and acrylic polymer copolymer, such as aminoalkyl methacrylate copolymer E, etc., is disclosed in EP 413,299 (corresponds to Japanese Kokai Patent No. Hei 3-74396).
Moreover, an invention pertaining to a method of producing a solid dispersion of a slightly soluble drug comprising this drug and aminoalkyl methacrylate copolymer E using a biaxial extruder is disclosed in U.S. Pat. No. 5,456,923.
Nevertheless, these technologies only increase solubility of a drug and as a result, improve oral absorption by making the above-mentioned dispersion. They do not use the function of aminoalkyl methacrylate copolymer E of improving digestive tract absorption of drugs in the mucous layer and mucous membrane of the digestive tract.
In addition, these patent gazettes do not disclose or suggest technology that realizes excellent absorption from the mucous layer and mucous membrane of the digestive tract by uniformly mixing aminoalkyl methacrylate copolymer E and acidic substance.
An invention whereby a core comprising the acid addition salt of a basic drug is coated by a compound of weak alkalinity to bring pH to the neutral or alkaline region where drug solubility is good and as a result, bitter taste is improved and drug absorptivity is improved, and aminoalkyl methacrylate copolymer E is used as the coating agent and binder is disclosed in Japanese Kokai Patent No. Hei 4-327529.
Nevertheless, this technology does not use the function of aminoalkyl methacrylate copolymer E of improving absorptivity from the mucous layer and mucous membrane of the digestive tract.
In addition, this patent gazette dose not disclose technology by which improvement to realize excellent absorption from the mucous layer and mucous membrane of the digestive tract by uniformly mixing aminoalkyl methacrylate copolymer E and acidic substance.